Absence of the glucagon-like peptide-1 receptor does not affect the metabolic phenotype of mice with liver-specific Gsα deficiency

Abstract

The stimulatory G protein α-subunit (Gsα) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver- Specific Gsα deficiency [liver-specific Gsα knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon- Like peptide 1 (GLP- Like peptide1 promotes DNA synthesis, activates phosphatidylinositol 3Kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX1) DNA binding activity in β(INS1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r-/-) and compared LGsKO to double-knockout (LGs/Glp1r-/-) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific Gsα deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver Gsα/cAMP pathway and pancreatic islet function need to be further elucidated. Copyright © 2011 by The Endocrine Society.